The neuronal calcium sensor-1 (NCS-1) is an intracellular calcium sensor of the EF-hand calcium-binding proteins family that is neuron-specific and highly conserved throughout evolution with 100% identity at the amino acid level among vertebrates, and 75% between vertebrates and C. elegans (Braunewell and Gundelfinger, 1999; De Castro et al., 1995). NCS-1 binds 3 calcium ions with a high affinity of ˜300 nM that is within the range of intracellular Ca2+i fluctuations known to regulate key neuronal functions such as neurotransmitter release, receptor phosphorylation, ion channel activities, or transcription (Bourne et al., 2001; Burgoyne and Weiss, 2001; Cox et al., 1994; Fontana and Blaustein, 1993; Martone et al., 1999; Paterlini et al., 2000; Yazejian et al., 2000). In a calcium-dependent manner, the recombinant vertebrate NCS-1 can activate, in vitro, the G-protein receptor kinase 1 (De Castro et al., 1995; lacovelli et al., 1999), substitute for calmodulin (CaM) and directly activate CaM-dependent targets such as 3′:5′-cyclic nucleotide phosphodiesterase, calcineurin, and nitric oxide synthase enzymes (Schaad et al., 1996). NCS-1 has also been reported to regulate evoked exocytosis in neuroendocrine cells (McFerran et al., 1998). Phenotypic analyses addressing the functional role of NCS-1 in vivo have been performed with yeast, Paramecium, C. elegans, and Drosophila. In S. cerevisiae, the frq1 gene encodes NCS-1 which is essential for vegetative growth, and which has been shown, following genetic studies, to interact with the yeast phosphatidylinositol 4-OH kinase Pik1 (Hendricks et al., 1999). The vertebrate NCS-1 directly substitutes for a mutated form of CaM in Paramecium and can restore normal wild-type (WT) behavioral responses (avoiding reaction) of live Paramecium mutants most likely via the re-activation of a CaM-dependent potassium channel (Schaad et al., 1996). A shaker-like phenotype in Drosophila caused by the overexpression of frequenin (Pongs et al., 1993), the Drosophila orthologue of NCS-1, seems to involve an increase of evoked neurotransmitter release at the neuromuscular junction (NMJ) of flies via unknown mechanisms that could possibly involve the NCS-1-dependent regulation of a K+ channel (Poulain et al., 1994) or of a Na+-Ca2+ exchanger (Rivosecchi et al., 1994). However, the function of NCS-1, if any, in terms of particular phenotypic characteristics responsive to NCS-1 activity remained unknown.